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  • mi2 Considerable work has gone into evaluating the impact of

    2018-11-09

    Considerable work has gone into evaluating the impact of putative adjuvants on innate immune activation and on adaptive immune responses to model mi2 and potential vaccines (Longhi et al., 2009; Kastenmuller et al., 2012; Trumpfheller et al., 2008; Stahl-Hennig et al., 2009; Perret et al., 2013; Caproni et al., 2012). It has been demonstrated that co-administration of adjuvant and antigen can be critical for optimizing the immune response, and formulation of adjuvants and antigen in nanoparticles for co-administration is currently being explored as a means of targeting the adjuvant effects (Quinn et al., 2013b; Hanson et al., 2015; Moon et al., 2012; Jain et al., 2011). However, adjuvants\' impact on long lasting protective immunity is poorly understood, particularly in the context of a relevant challenge model (Seder et al., 2015). The filovirus VLP vaccine has demonstrated efficacy in the murine, guinea pig, and nonhuman primate models of filovirus infection (Swenson et al., 2005, 2008a, 2008b; Warfield et al., 2003, 2004, 2007; Martins et al., 2014, 2015a). To evaluate durable protection, we developed a rigorous murine model for Ebola virus challenge. We then tested the ability of the aforementioned adjuvants to augment protection under this model. Correlates of durable protection were identified by comparing and contrasting immune parameters associated with different levels of protection. These data inform broadly on the impact of classic TLR agonists to enhance the durable protection of a protein-based vaccine, and they demonstrate that adjuvant selection can determine the quality and utility of a vaccine candidate.
    Methods
    Results
    Discussion In terms of antibody response, a Th1-skewed antibody response correlated with protection. Vaccination with VLP and polyICLC yielded significantly higher IgG2c titers than vaccination with any other vaccine and adjuvant combination. In contrast, vaccination with alhydrogel and VLP, which had no impact on survival, resulted in a Th2 skewed antibody response. To further examine the impact of antibody on survival, NAb titers were examined. NAb are associated with protection in several vaccination models (Roy et al., 2015; van Gils and Sanders, 2014; Kok et al., 2014; Plotkin, 2010), but data regarding the importance of NAb in EBOV protection are conflicting (Wong et al., 2012; Sullivan et al., 2009; Audet et al., 2014; Oswald et al., 2007; Grant-Klein et al., 2015; Lee et al., 2008; Bale et al., 2012; Martins et al., 2015a; Agnandji et al., 2015). Interestingly, NAb titers had no relationship to survival in this durable protection model. Both polyICLC and alhydrogel substantially impacted NAb titers and improved survival on a short term timescale; however, only polyICLC had a beneficial impact on durable protection. This examination of antibody feeds into a larger discussion on the role of neutralization and the definition of neutralizing antibody. The assay utilized in this study includes supplementation with complement, which complicates the definition of neutralization. Despite this fact, neutralization still did not correlate with survival while IgG2c titers did, suggesting an under-appreciated role for non-neutralizing antibody in controlling infection under a durable protection model. Previous work has demonstrated that CD4 T cells may be important for Ebola-mediated protection (Wong et al., 2012; Rao et al., 2002). However, dissecting the role of CD4 T cells in protective immunity is challenging due to their impact on the development of high affinity antibody responses and effective CD8 T cell responses (Sant and McMichael, 2012). CD4 T cells also have an effector function and are critical for immune cell recruitment during infection (Soghoian and Streeck, 2010; McKinstry et al., 2012; Brown et al., 2012; Johnson et al., 2015). Recently, an appreciation for the importance of CD4 T cells in viral infection has grown, particularly in the context of influenza vaccination (Zens and Farber, 2015). Antigen-specific CD4 T cells were associated with lower viremia during human influenza infection (Wilkinson et al., 2012), and, in nonhuman primates, CD4 T cell populations were important in Hepatitis A clearance (Zhou et al., 2012). Because of the complex role of CD4 T cells in the immune response, the impact of adjuvants on CD4 T cell responses has also been extensively examined (Baumgartner and Malherbe, 2010; McAleer and Vella, 2010). Both TLR agonist adjuvants and aluminum-containing adjuvants have been associated with CD4 T cell efficacy (Monaci et al., 2015; Sokolovska et al., 2007).